DESIGN & DEVELOPMENT OF RECOMBINANT VACCINES FOR CANCER IMMUNOTHERAPY

设计

• 批准号: 6160874
• 负责人: J SCHLOM
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6160874
• 关键词: breast neoplasms; carcinoembryonal antigen; chimeric proteins; clinical research; clinical trial phase I; cytotoxic T lymphocyte; drug design /synthesis /production; gene therapy; helper T lymphocyte; human subject; lung neoplasms; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; oncogenes; oncoproteins; pancreatic islet neoplasm; point mutation; prostate specific antigen; protooncogene; recombinant proteins; recombinant virus; tissue /cell culture; vaccine development; vaccinia virus

Research involves the development of novel immunotherapeutic approaches to cancer, including the design and analyses of recombinant vaccines directed against gene products of oncogenes and antigens overexpressed in tumors. Vaccine targets include human carcinoembryonic antigen (CEA), point mutated ras oncogenes, prostate specific antigen (PSA), and the muc-1 breast, lung, and pancreatic associated mucin. Vehicles for vaccine delivery for induction of host cellular immune responses include recombinant vaccinia (rV), replication defective avian pox viruses (avipox), immunodominant peptides, and recombinant proteins. Phase I clinical trials have now demonstrated that when advanced carcinoma patients are vaccinated with recombinant vaccinia virus or recombinant avipox containing the CEA gene, cytotoxic T-cell (CTL) responses are induced to the self antigen CEA. The actual epitopes recognized by these T-cells have now been defined and used to establish CEA-specific CTL lines and clones. The utility of these and other CTL lines in the adoptive transfer of epitope specific T-cells is currently under investigation.Vaccine trials employing CEA CTL peptides, either in adjuvant or pulsed on dendritic cells, are in progress.Studies are ongoing in the elucidation and analyses of agonist peptides of the identified CEA CTL immunodominant epitopes. Initial studies have indicated that peptides can be designed that are more efficient than the natural peptide in the generation of cytotoxic T-cell lines. Clinical trials are also ongoing in prostate cancer patients with a recombinant vaccinia PSA vaccine. PSA CTL immunodominant epitope peptides have also recently been identified in in vitro studies. A Phase I clinical trial is now in progress in which peptides reflecting ras oncogene point mutations at codon 12 are administered to patients whose tumors have been shown to contain the individual mutation. These studies have shown the induction of both CD4+ helper T-cells and CD8+ CTL specific for the mutated ras peptide and not proto-ras. Ongoing preclinical studies include the use of multidimensional fusion proteins as immunogens and the exploitation of T-cell co-stimulatory molecules in pox virus vectors in both gene therapy and vaccine strategies.

研究涉及开发新的免疫治疗方法 癌症，包括重组疫苗的设计和分析 针对癌基因和抗原过度表达的基因产物 在肿瘤中。疫苗靶标包括人类癌胚抗原(CEA)， 点突变的ras癌基因、前列腺特异性抗原(PSA)和 MUC-1乳腺、肺和胰腺相关粘蛋白。交通工具 用于诱导宿主细胞免疫反应的疫苗递送包括 重组痘苗病毒(RV)、复制缺陷禽痘病毒 (禽痘)、免疫优势多肽和重组蛋白。第一阶段 临床试验现在已经证明，当晚期癌症 患者接种重组牛痘病毒或重组牛痘病毒 含有CEA基因的禽痘，细胞毒性T细胞(CTL)反应是 诱导产生自身抗原CEA。它们所识别的实际表位 T细胞现已被定义并用于建立CEA特异性CTL 线条和克隆。这些线路和其他CTL线路在 表位特异性T细胞的过继转移目前正在进行中 研究：使用CEA CTL多肽的疫苗试验 树突状细胞佐剂或脉冲剂的研究正在进行中。 正在进行的阐明和分析的激动肽的 确定了CEA CTL免疫优势表位。初步研究表明 表明可以设计出比 天然多肽在细胞毒T细胞系中的生成。临床 对前列腺癌患者的试验也在进行中， 牛痘PSA疫苗。PSA CTL免疫优势表位多肽也 最近在体外研究中被发现。一期临床试验 目前正在研究反映ras癌基因点的多肽 密码子12的突变适用于肿瘤患者 被证明含有个体突变。这些研究表明 CD_4~+辅助性T细胞和CD_8~+CTL的诱导 突变的ras多肽，而不是原ras。正在进行的临床前研究 包括使用多维融合蛋白作为免疫原和 T细胞共刺激分子在痘病毒载体中的开发 在基因治疗和疫苗策略方面。